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 Articles

Compression stockings to prevent post-thrombotic

syndrome: a randomised placebo-controlled trial
Susan R Kahn, Stan Shapiro, Philip S Wells, Marc A Rodger, Michael J Kovacs, David R Anderson, Vicky Tagalakis, Adrielle H Houweling,
Thierry Ducruet, Christina Holcroft, Mira Johri, Susan Solymoss, Marie-José Miron, Erik Yeo, Reginald Smith, Sam Schulman, Jeannine Kassis,
Clive Kearon, Isabelle Chagnon, Turnly Wong, Christine Demers, Rajendar Hanmiah, Scott Kaatz, Rita Selby, Suman Rathbun, Sylvie Desmarais,
Lucie Opatrny, Thomas L Ortel, Jeffrey S Ginsberg, for the SOX trial investigators

Summary
Background Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis Published Online
(DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single- December 6, 2013
http://dx.doi.org/10.1016/
centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for
S0140-6736(13)61902-9
the prevention of PTS.
See Online/Comment
http://dx.doi.org/10.1016/
Methods We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to S0140-6736(13)62347-8
prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study Centre for Clinical
groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were Epidemiology, Jewish General
Hospital, Montreal, QC, Canada
potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they
(S R Kahn MD, S Shapiro PhD,
had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they V Tagalakis MD,
were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The A H Houweling MSc,
primary outcome was PTS diagnosed at 6 months or later using Ginsberg’s criteria (leg pain and swelling of ≥1 month T Ducruet MSc); Department of
Epidemiology and
duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol
Biostatistics, McGill University,
analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials. Montreal, QC, Canada
gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. (S Shapiro); Department of
Medicine, University of
Ottawa/Ottawa Hospital,
Findings From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The
Ottawa, ON, Canada
cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre (P S Wells MD); Ottawa Hospital
1·13, 95% CI 0·73–1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported Research Institute, Ottawa,
frequent use of stockings. ON, Canada (P S Wells,
M A Rodger MD); Thrombosis
Program, Division of
Interpretation ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing Hematology, Department of
of ECS after DVT. Medicine, University of
Ottawa, Ottawa, ON, Canada
(M A Rodger); Division of
Funding Canadian Institutes of Health Research. Hematology, London Health
Sciences Centre, London, ON,
Introduction 2 years after proximal DVT halved the risk of developing Canada (M J Kovacs MD);
Post-thrombotic syndrome (PTS) is a chronic disorder PTS. However, both trials were small, done in a single Department of Medicine,
Dalhousie University, Halifax,
that develops in 25–50% of patients after deep venous centre, and were not placebo-controlled. Stockings are NS, Canada (D R Anderson MD);
thrombosis (DVT).1,2 Its clinical features range from cumbersome to apply, and can be hot, constricting, and Capital Health, Halifax, NS,
minor limb swelling and discomfort to severe leg pain, itchy. They can cost $100 or more per pair, need to be Canada (D R Anderson); The
intractable oedema, irreversible skin changes, and leg replaced twice a year due to wear and tear, and might Institute for Clinical Research
and Health Policy Studies, Tufts
ulceration. PTS reduces quality of life3,4 and imposes a not be covered by public health care plans. Furthermore, Medical Center, Boston, MA,
substantial economic burden on patients and society.5,6 a survey of thrombosis physicians showed a lack of USA (C Holcroft ScD); Tufts
Prevention of PTS is important since treatments are agreement on the benefits of ECS or the optimum Clinical and Translational
not very effective.7,8 Ideally, PTS is averted entirely by timing, indication, and duration of their use.12 In view of Science Institute, Tufts
University, Boston, MA, USA
primary prevention of the initial DVT with the judicious the above, we believed that a large, placebo-controlled (C Holcroft); International
use of thromboprophylaxis. However, thromboprophyl- trial was needed to provide definitive evidence of Health Unit, University of
axis remains underused and the occurrence of at least efficacy, or lack of efficacy, of ECS. This would allow Montreal Hospital Research
half of all cases of DVT are unpredictable, hence are not physicians to make informed, evidence-based decisions Centre, Montreal, QC, Canada
(M Johri PhD); Department of
preventable. Therefore, prevention of PTS after DVT is on the use of compression stockings in patients with Health Administration, Faculty
an important goal. DVT. We therefore did the SOX trial, a multicentre, of Medicine (M Johri), and
Elastic compression stockings (ECS) have the potential randomised, placebo-controlled trial to establish Department of Medicine,
Hôpital du Sacré-Coeur
to prevent PTS by reducing venous hypertension and whether ECS prevent PTS after proximal DVT. We also
(I Chagnon MD), University of
reflux, which are thought principal factors in the assessed the effect of ECS on severity of PTS, recurrent Montreal, Montreal, QC,
pathophysiology of PTS.9 The findings of two previous venous thromboembolism, venous valvular reflux, and Canada; Division of
randomised trials10,11 suggested that wearing ECS for quality of life. Hematology, Montreal General

www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9 1

 Articles
Hospital, Montreal, QC, Canada
(S Solymoss MD); St Mary’s
Hospital, Montreal, QC, Canada
(S Solymoss); Professional
Services, St Mary’s Hospital
Center, Montreal, QC, Canada
(L Opatrny MD); Department of
Medicine, Hôpital Notre-Dame,
Montreal, QC, Canada
(M-J Miron MD); Division of
Hematology, University Health
Network, Toronto, ON, Canada
(E Yeo MD); Divisions of
Cardiology and Thrombosis,
Victoria Heart Institute
Foundation, Victoria, BC,
Canada (R Smith PharmD);
Department of Medicine,
McMaster University,
Hamilton, ON, Canada
(S Schulman MD, C Kearon MB,
J S Ginsberg MD); Thrombosis
and Atherosclerosis Research
Institute, Hamilton, ON,
Canada (S Schulman);
Karolinska Institute,
Stockholm, Sweden
(S Schulman); Division of
Hematology, Hôpital
Maisonneuve-Rosemont, QC,
Canada (J Kassis MD);
Department of Medicine,
St Boniface General Hospital,
University of Manitoba,
Winnipeg, Manitoba, Canada
(T Wong MD); Division of
Hematology, CHU de Quebec,
Quebec, QC, Canada
(C Demers MD); Division of
General Internal Medicine,
St Joseph’s Hospital, Hamilton,
ON, Canada (R Hanmiah MD);
Academic Hospital Medicine,
Hurley Medical Center, Flint,
MI, USA (S Kaatz DO);
Department of Medicine and
Department of Clinical
Pathology, Sunnybrook Health
Sciences Centre and University
Health Network, University of
Toronto, Toronto, ON, Canada
(R Selby MBBS); Department of
Medicine, Oklahoma University
Health Sciences Center,
Oklahoma City, OK, USA
(S Rathbun MD); Department of
Medicine, Hôpital Pierre-
Boucher, Longueuil, QC, Canada
(S Desmarais MD); and Division
of Hematology, Duke
University Medical Center,
Durham, NC, USA (T L Ortel MD)
Correspondence to:
Dr Susan R Kahn, Centre for
Clinical Epidemiology, Jewish
General Hospital, 3755 Cote Ste
Catherine Room H420.1,
Montreal, QC H3T 1E2, Canada
susan.kahn@mcgill.ca
See Online for appendix
2 www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9
Methods Randomisation and masking
Participants Patients were randomly assigned to study groups with a
Between June, 2004, and February, 2010, we enrolled web-based randomisation system (TrialStat, Jubilant
patients in 24 centres in Canada and the USA. The study Clinsys, Ottawa, ON, Canada), which ensured concealed
originally had a two by two factorial design that tested a allocation. Randomisation was stratified by centre and
second intervention, celecoxib versus placebo taken used varying block sizes of four and eight. At random-
twice-daily for 30 days. Because of concerns about the isation, an alert was sent to the stocking manufacturer’s
safety of COX-2 inhibitors13 it was decided to abandon central distribution centre (Sigvaris, St Laurent, QC,
this intervention after 26 patients were enrolled and Canada) with the patient’s treatment code, leg measure-
redesign the study as a parallel group trial of active versus ments, and mailing address. A pair of active or placebo
placebo ECS.14 stockings was then shipped directly to the patient. This
Patients presenting with a first symptomatic, proximal procedure was repeated during follow-up.
DVT (with or without concurrent distal DVT or pul- Treatment allocation was masked from patients, health-
monary embolism) were potentially eligible to partici- care providers, study personnel, and study statisticians. To
pate. Proximal DVT, which was defined as DVT in the assess masking, the patient, health-care providers, and
popliteal or more proximal deep leg veins, had to be study personnel were asked to state at the end of the study
objectively confirmed with ultrasound within the pre- which treatment they believed the patient had been
vious 14 days. Patients were excluded if they had a assigned to receive: active ECS, placebo ECS, or uncertain.
contraindication to the use of compression stockings
(eg, allergy or severe arterial claudication), an expected Procedures
lifespan of less than 6 months, geographical inaccess- Patients were randomly assigned to receive active
ibility precluding return for follow-up visits, were 30–40 mm Hg graduated ECS or placebo stockings with
unable to apply stockings, or received thrombolytic an identical appearance but less than 5 mm Hg com-
therapy for the initial treatment of acute DVT. The pression at the ankle (appendix). Stockings were applied
study was approved by the research ethics boards at all within 2 weeks of DVT diagnosis and were replaced every
participating centres, and written informed consent was 6 months, or earlier if stockings had torn or leg size had
obtained from all patients. changed. Patients were asked to wear the stocking on the
4012 patients assessed for eligibility 1265 declined to participate
1941 were excluded (some for >1 reason)
127 had more than 14 days since diagnosis of DVT
133 not planned for anticoagulant therapy
43 had symptomatic arterial claudication
575 had an expected lifespan of less than 6 months
379 were unable to apply the stockings
15 planned for thrombolysis of acute DVT
261 were geographically inaccessible for follow-up
488 were unable to provide informed consent
66 met exclusion criteria related to celecoxib
intervention (discontinued)
806 randomly assigned to receive intervention
410 assigned to receive active ECS 396 assigned to receive placebo ECS
408 received allocated intervention 392 received allocated intervention
1 did not receive allocated intervention 2 did not receive allocated intervention
1 was ineligible (excluded from analysis) 2 were ineligible (excluded from analysis)
23 were lost to follow-up 21 were lost to follow-up
33 withdrew from the study 37 withdrew from the study
36 died 36 died
409 assessed 394 assessed
Figure 1: Trial profile
Three patients were ineligible and excluded from the analysis (in the active ECS group, one patient had no DVT [did not receive study stockings] and in the
placebo ECS group, one patient had previous DVT [did not receive study stockings] and one was moribund [received study stockings]). Three patients did not
receive their allocated intervention. Because of leg shape, one patient in each group could not be fitted with stockings; they did not receive stockings but
continued in the trial. One patient in the placebo ECS group received active ECS at the baseline visit due to an error at the stockings distribution centre—the
patient insisted on using the same type of stockings throughout the trial without knowing if it was active or placebo. ECS=elastic compression stockings.
DVT=deep venous thrombosis.
 Articles

affected leg from waking until retiring for 2 years, and Statistical analysis
were encouraged to keep active. We estimated that the cumulative incidence of the primary
Co-interventions (anticoagulants, non-steroidal anti- outcome would be 30% in the placebo ECS group and
inflammatory drugs) and use of non-study stockings 20% in the active ECS group over the 2 year follow-up—ie,
were recorded at each study visit. Data on results of a risk reduction of 33%.15,24 These event rates were con-
international normalised ratio tests were not collected. verted into exponential distribution instantaneous hazard
Patients attended follow-up visits at 1, 6, 12, 18, and rates and the corresponding sample size was obtained by
24 months, and were instructed to not wear study
stockings to the visits. Visits were scheduled in the
afternoon when possible to allow PTS signs to become Active Placebo
fully evident. Frequency of stocking use between visits stockings group stockings group
(n=409) (n=394)
was recorded (number of days per week [response options
were every day, 3–6 days per week, 1–2 days per week, or Age, years 55·4 (15·3) 54·8 (15·8)

less than once per week] and numbers of hours per day). Age category
In the original study protocol, the primary outcome <40 years 67 (16·4%) 67 (17·0%)
was the proportion of patients with PTS at the 24 month 40–65 years 222 (54·3%) 217 (55·1%)
study visit. Before any analyses, the study’s steering >65 years 120 (29·3%) 110 (27·9%)
committee decided to change the primary outcome to Men 255 (62·4%) 228 (57·9%)
the cumulative incidence of PTS (ie, time to first event) Outpatients 355 (86·8%) 344 (87·3%)
from 6 to 24 months follow-up to optimally use all White ethnic origin 371 (90·7%) 354 (89·9%)
available outcome data (this change did not affect Body-mass index, kg/m² 29·0 (6·1) 28·9 (6·1)
the study’s sample size). PTS was diagnosed with Time from DVT diagnosis to randomisation, days 4·8 (4·1) 4·6 (3·8)
Ginsberg’s criteria of ipsilateral pain and swelling of at Characteristics of DVT
least 1 month’s duration that are typical in character Right 180 (44·0%) 173 (43·9%)
(worse at the end of the day or with prolonged sitting or Left 222 (54·3%) 216 (54·8%)
standing, and better after a night’s rest and leg Bilateral 7 (1·7%) 5 (1·3%)
elevation).15 Local study investigators were required to Most proximal extent of DVT*
confirm each case of PTS. Iliac vein 44 (10·8%) 49 (12·4%)
As secondary outcomes, we recorded cumulative Common femoral vein 109 (26·7%) 107 (27·2%)
incidence and severity of PTS with Villalta’s scale, Femoral vein 128 (31·3%) 123 (31·2%)
that grades the intensity (0 points=absent, 1=mild, Popliteal vein 128 (31·3%) 115 (29·2%)
2=moderate, 3=severe) of five patient-rated symptoms Villalta score at baseline 8·2 (4·4) 8·7 (4·8)
(pain, cramps, heaviness, pins and needles, and itching) Concurrent pulmonary embolism 57 (13·9%) 57 (14·5%)
and six physical signs (pretibial oedema, skin indura- Venous thrombosis risk factors
tion, hyperpigmentation, pain during calf compression, Surgery, past 3 months 77 (18·8%) 64 (16·2%)
venous ectasia, and redness).16–18 The presence of leg Trauma, past 3 months 42 (10·3%) 51 (12·9%)
ulcers was also recorded. Physical signs were assessed by Immobilised in past month 67 (16·4%) 61 (15·5%)
study nurses or physicians with the aid of a full-colour Active cancer† 52 (12·7%) 46 (11·7%)
visual guide.18 A higher total Villalta’s score suggests Pregnant, post partum, oral contraceptives, or hormonal 37 (24·0%) 55 (33·1%)
greater severity of PTS (a score ≥5 or a venous ulcer replacement therapy‡
suggests PTS; score of 5–9, mild PTS; 10–14, moderate Family history of venous thromboembolism 85 (20·8%) 82 (20·8%)
PTS; >15 or venous ulcer, severe PTS). DVT treatment
Additional secondary outcomes included objectively Low molecular weight heparin 388 (94·9%) 384 (97·5%)
confirmed recurrent venous thromboembolism, death, Unfractionated heparin 31 (7·6%) 21 (5·3%)
adverse events, venous valvular reflux, and quality of Warfarin 330 (80·7%) 317 (80·5%)
life. All suspected recurrent venous thromboembolism Investigational anticoagulant§ 15 (3·7%) 11 (2·8%)
events and deaths were independently adjudicated by Duration of heparin, days 8 (6–11) 8 (6–10)
two physicians from whom treatment allocation was Duration of warfarin, days 186 (113–240) 180 (100–214)
masked (for diagnostic criteria see appendix). Adverse Duration of investigational anticoagulant§, days 189 (183–647) 205 (182–546)
events were classified as likely or unlikely to be due to
Duration of oral anticoagulation (warfarin or investigational), days 186 (113–253) 182 (104–220)
study stockings. Venous valvular reflux at the popliteal
vein was assessed as present or absent at the 12 month Data are n (%), mean (SD), or median (IQR). DVT=deep vein thrombosis. *In the case of bilateral DVT, the leg with the
most proximally extensive DVT was used as the index leg. †Diagnosed within past 6 months, treatment ongoing,
visit with a standardised venous ultrasound procedure
metastatic, or palliative. ‡In women only (active ECS, 154 women; placebo ECS, 166 women). §Some patients were
(for description of procedure see appendix).19,20 Quality of participants in concurrent studies comparing investigational anticoagulants (oral dabigatran, oral rivaroxaban, or
life was measured at each study visit with validated subcutaneous idraparinux) with standard anticoagulation.
generic (SF-36)21 and venous-disease specific (VEINES-
Table 1: Baseline characteristics
QOL/Sym)22,23 questionnaires.

www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9 3

 Articles

use of the approach of Schoenfeld and Richter,25 as imple-
mented by the program PS Power and Sample Size.26 The
total sample size needed to detect a difference between
groups with a two-tailed α of 0·05 and 80% power was
800, which included adjustment for a projected 25% rate
of loss-to-follow up, including deaths.
The Data Safety Monitoring Board regularly reviewed
study recruitment, patient retention, and safety out-
comes. A single, planned, formal masked interim analy-
sis to consider early stopping for efficacy was done after
364 patients completed follow-up, and employed a Lan-
DeMets α-spending approach using an O’Brien-Fleming
spending function.27 Based on the results of this analysis,
A mass index (BMI), and proximal extent of index DVT. In
100
90
80
post-thrombotic syndrome (%)
the Data Safety Monitoring Board recommended that
patient recruitment should continue to complete the
originally planned sample size of 800 patients.
Cumulative incidences of PTS (primary analysis) were
compared in a modified intention-to-treat analysis with
Cox regression adjusted for centre. Losses to follow-up,
withdrawals, and deaths were censored as of last date of
follow-up. This was supplemented by a prespecified per-
protocol analysis of patients who reported frequent use of
their allocated treatment. Patients were classified as
frequent users if they used study stockings for at least
3 days per week at three or more of five study visits, or at
two or more study visits if there were fewer than five visits.
We did prespecified subgroup analyses by age, sex, body-
Active ECS secondary analyses, we compared the cumulative inci-
Placebo ECS dence of PTS as assessed by a Villalta score of 5 or higher
at the 6 month visit or later18 using Cox regression adjusted

for centre. For both groups, we also described severity of

Cumulative incidence of

70
PTS, the proportion who developed venous ulcers, recur-
60 rent venous thromboembolism, death from venous
50 thromboembolism, adverse events attributed to study
40 stockings, and venous valvular reflux at 12 months. t tests
30
were used to compare within-patient changes in quality of
life scores from baseline to time of last follow-up. In
20
sensitivity analyses to assess the effect of missing quality
10
of life data, logistic regression was done to estimate the
0
0 182 365 547 730
probability of missingness for each timepoint, by
treatment group. Baseline variables age, sex, inpatient
Number at risk
Active ECS 403 352 317 294 183 status, ethnicity, BMI, concurrent pulmonary embolism,
Placebo ECS 392 340 311 289 179 trauma, surgery, immobilisation, cancer, and extent of
DVT were used as independent predictors in the model.
B We then did a weighted analysis based on the inverse
100
probability of missingness using a generalised estimated
90
equation.28 Since the results were similar to the un-
80 weighted analyses, the latter results are reported.
post-thrombotic syndrome (%)

All statistical tests were two-sided and significance was

Cumulative incidence of

70
60 set at p<0·05. Analyses were done with SAS version 9.3.
50
This study is registered with ClinicalTrials.gov, number
NCT00143598, and Current Controlled Trials, number
40
ISRCTN71334751.
30
20 Role of the funding source
10 The sponsor of the study had no role in study design,
0 data collection, data analysis, data interpretation, or
0 182 365 547 730 writing of the report. The corresponding author had full
Time since randomisation (days)
Number at risk access to all the data in the study and had final
Active ECS 403 318 224 183 109
Placebo ECS 392 302 212 178 109
responsibility for the decision to submit for publication.

Figure 2: Cumulative incidence of post-thrombotic syndrome Results

The primary outcome (A; Ginsberg’s criteria) was first assessed at the 6 month visit and each 6 months thereafter.
Figure 1 shows the trial profile. Three patients were
Cumulative incidence of PTS (at 750 days) was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio [HR]
adjusted for centre 1·13, 95% CI 0·73–1·76; p=0·58). The secondary outcome (B), PTS diagnosed using Villalta’s identified as ineligible soon after randomisation and
criteria, was first assessed at the 6 month visit and each 6 months thereafter. Cumulative incidence of PTS by were excluded from further analysis (ie, modified
Villalta’s criteria (Villalta score ≥5 or ulcer at or after the 6 month visit; at 750 days) was 52·6% in active ECS versus intention-to-treat). Baseline characteristics were similar
52·3% in placebo ECS (HR adjusted for centre 1·00, 95% CI 0·81–1·24; p=0·96). For both criteria, data from patients
between the two groups (table 1). Overall, 483 (60·1%) of
who withdrew consent or who were lost to follow-up were censored at the time of the last follow-up assessment,
and patients who stopped study stockings but agreed to follow-up were included in the intention-to-treat 803 patients were men, mean age was 55·1 years
analysis. PTS=post-thrombotic syndrome. ECS=elastic compression stockings. (SD 15·5), and 699 (87·1%) of 803 were outpatients.

4 www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9

 Articles

Mean time from DVT diagnosis to randomisation was
4·7 days (SD 3·9). The most proximal extent of DVT was
iliac vein in 93 (11·6%) of 803 patients, common femoral
vein in 216 (26·9%), femoral vein in 251 (31·3%), and
popliteal vein in 243 (30·3%).
The cumulative incidence of PTS (Ginsberg’s criteria)
during study follow-up was 14·2% in the active ECS
group versus 12·7% in the placebo ECS group (figure 2,
table 2). In secondary analyses, there were no between-
group differences in the cumulative incidence of PTS
defined with Villalta’s scale (figure 2), distribution of PTS
severity category, or rate of ipsilateral leg ulcers. Rates of
recurrent episodes of venous thromboembolism, ipsi-
lateral DVT, and death were similar in both groups, as
was the prevalence of ipsilateral venous valvular reflux at
12 months (table 2). Mean Villalta total scores, symptom
scores, sign scores, and severity category at each study
visit were similar between groups (appendix).
Generic and disease-specific quality-of-life scores were
similar between groups at each visit (appendix). Within-
patient changes in quality-of-life scores from baseline to
last follow-up visit did not differ between groups. SF-36
physical component score improved by 8·4 points
(SD 13·6) for active ECS versus 9·9 (SD 13·2) for placebo
ECS (difference between groups of –1·53 points, 95% CI
–3·44 to 0·39; p=0·12). SF-36 mental component score
improved by 1·6 points (SD 12·3) for active ECS versus
1·8 (SD 11·4) for placebo ECS (difference of –0·23 points,
95% CI –1·94 to 1·47; p=0·79). VEINES-QOL score
improved by 5·8 points (SD 7·5) for active ECS versus
5·9 (SD 7·1) for placebo ECS (difference of –0·12 points,
95% CI –1·11 to 0·86; p=0·81).
Most patients received standard anticoagulant therapy
consisting of 5–10 days of heparin (usually subcutaneous
low molecular weight heparin) and warfarin for
3–6 months or longer to treat their acute DVT. Median
duration of anticoagulation was similar in the two groups
(186 days [IQR 113–253] for active ECS and 184 days
[104–220] for placebo ECS; table 1). Similar proportions of
patients in each group reported taking oral anticoagulants,
heparins, and non-steroidal anti-inflammatory drugs at
each visit. Temporary use of non-study stockings was
uncommon (appendix).
Use of study stockings at each visit was similar
between groups. Overall, at 1 month, 734 (96·1%) of
764 patients reported wearing their stockings, and, of
these, 660 (86·4%) of 764 used them for 3 or more days
per week; this decreased to 378 (69·1%) of 547 and
304 (55·6%) of 547, respectively, by the 24 month visit.
When used, stockings were worn for about 10–11 h per
day (appendix).
Attendance at study visits was similar in both groups
(appendix). Over the course of the study, 33 patients in
the active ECS group withdrew from the study (ie, did not

Active stockings (n=409) Placebo stockings (n=394) Hazard ratio*

(95% CI)
Primary outcome
Number of post-thrombotic syndrome events as assessed 44 (14·2%) 37 (12·7%) 1·13 (0·73–1·76)
by Ginsberg’s criteria† (cumulative incidence‡)
Secondary outcomes
Number of post-thrombotic syndrome events as assessed 176 (52·6%) 168 (52·3%) 1·00 (0·81–1·24)
by Villalta’s criteria§ (cumulative incidence‡)
Villalta severity category¶
None (score <5) 185 (51·3%) 178 (51·4%) ··
Mild (5–9) 119 (33·0%) 111 (32·1%) ··
Moderate (10–14) 30 (8·3%) 37 (10·7%) ··
Severe (>14 or ulcer) 27 (7·5%) 20 (5·8%) ··
Ipsilateral leg ulcer|| 17 patients (4·2%); 17 ulcers 16 patients (4·1%); 17 ulcers ··
Recurrent venous thromboembolism 33 patients (8·1%); 45 events 38 patients (9·6%); 44 events ··
(36 DVT, 9 pulmonary embolism) (32 DVT, 12 pulmonary embolism)
Recurrent ipsilateral DVT 16 patients (3·9%); 18 events 17 patients (4·3%); 17 events ··
Ipsilateral venous valvular reflux at 12 months** 120/291 (41·2%) 117/283 (41·3%) ··
Death†† 36 (8·8%) 36 (9·1%) ··

DVT=deep vein thrombosis. *Adjusted for centre. Of the 803 patients in the intention-to-treat analysis, 795 were included in the time-to-event analysis. The eight patients
(six in the active stockings group and two in the placebo stockings group) who were not included are those for whom no follow-up data were available after the baseline visit.
†Pain and swelling of 1 or more month’s duration that is typical in character (worse at the end of the day or with prolonged sitting or standing, and better after a night’s rest
and leg elevation).15 ‡Cumulative incidence as of 750 days follow-up. §Villalta score ≥5 or ulcer at or after the 6 month visit.16,18 ¶Highest Villalta score at or after 6 month visit
(missing for 48 patients in each group). Patients with a venous ulcer whose total Villalta score was less than 15 were attributed a score of 15.18 ||In the active stockings group,
two cases of leg ulcer were noted at the 1 month visit, six at the 6 month visit, seven at the 12 month visit, and two at the 24 month visit. In the placebo stockings group, five
cases of leg ulcer were noted at the 1 month visit, seven at the 6 month visit, two at the 12 month visit, two at the 18 month visit, and one at the 24 month visit. **A total of
574 patients underwent ultrasound assessment for venous valvular reflux at 12 months. ††No deaths in either group were judged by investigators to be definitely or probably
due to pulmonary embolism, or judged by adjudicators to be attributable (primary or contributing cause) to pulmonary embolism.

Table 2: Outcomes by treatment group

www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9 5

 Articles
wish further contact) compared with 37 in the placebo
group and 23 were lost to follow-up compared with 21 in
the placebo group.
A comparison of the cumulative incidence of PTS in
patients in each group who reported frequent use of
stockings (per-protocol analysis) yielded similar results
(hazard ratio for primary outcome, adjusted for centre,
0·96, 95% CI 0·53–1·74; appendix). Prespecified sub-
group analyses by age, BMI, and extent of DVT did not
detect differences between the study groups. For sex, the
test for interaction was marginally statistically significant
(p=0·047), suggesting treatment benefit for women
(figure 3). To explore this finding, in post-hoc analyses
we assessed whether stockings use differed by sex; at
each study visit, men reported more common use of
stockings than women (appendix) and 286 (59·2%) of
483 men versus 162 (50·6%) of 320 women met our
definition of frequent users of stockings.
There were no serious adverse events attributable to
stockings in either group. Minor adverse events (rash,
itching) occurred in eight patients in the active ECS
group and seven patients in the placebo ECS group.
In the active ECS group, 202 (59%) of 345 patients,
300 (76%) of 394 research nurses, and 334 (87%) of
382 site investigators provided either a wrong guess or
answered “uncertain” about whether patients were wear-
ing active or placebo stockings, suggesting that they
remained unaware of treatment allocation. The propor-
tion of correct responses in the active ECS group for
patients was 41% (143 of 345), research nurses 24% (94 of
394), and site investigators 13% (48 of 382).
In the placebo ECS group, 279 (83%) of 336 patients,
336 (88%) of 380 research nurses, and 341 (92%) of
371 site investigators provided either a wrong guess or
Hazard ratio (95% CI)
Sex
Male (n=478)
Female (n=317)
BMI
<25 (n=210)
25–30 (n=303)
>30 (n=282)
Age category (years)
<40 (n=132)
40–65 (n=435)
>65 (n=228)
Most proximal extent of DVT
Iliac or common femoral vein (n=307)
Femoral or popliteal vein (n=488)
Overall (n=795)
0·1 0·2 0·5 1 2
Favours active stockings Favours placebo stockings
Figure 3: Analysis of prespecified subgroups
For all subgroup treatment effects, 95% CIs overlapped each other and the null. Test of interaction p value was
p=0·047 for sex, p=0·38 for age, p=0·60 for BMI, and p=0·55 for extent of deep venous thrombosis.
BMI=body-mass index.
6 www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9
answered “uncertain” about whether patients were
wearing active or placebo stockings, suggesting that they
remained unaware of treatment allocation. The propor-
tion of correct responses in the placebo ECS group for
patients was 17% (57 of 336), research nurses 12% (44 of
380), and site investigators 8% (30 of 371).
Discussion
Our findings show that wearing a graduated ECS did not
reduce the incidence of PTS at 2 years in patients with a
first proximal DVT, compared with wearing placebo
stockings. Similarly, ECS did not affect the occurrence of
venous ulcers, rate of recurrent venous thromboembol-
ism, prevalence of venous valvular reflux at 12 months,
or generic or venous disease specific quality of life. These
findings were consistent across subgroups defined by
age, BMI, and extent of DVT. We believe a true subgroup
effect for sex is unlikely because the test of interaction p
value was only slightly significant and the CIs
surrounding the hazard ratios for men and women
overlapped and crossed the null. Frequency of use of
study stockings was very high initially, diminished over
time, and was similar in the two groups. In a prespecified
per-protocol analysis that focused on patients who used
stockings more commonly, we did not identify evidence
of benefit of active ECS. In post-hoc analyses, use of a
more strict definition of frequent use (daily use at all
study visits) similarly did not show evidence of benefit of
active ECS (data not shown). Taken together, our findings
suggest that ECS do not alter the natural history of
development of PTS after DVT.
The cumulative incidence of PTS in both groups was
lower than that reported in some previous studies. This
is probably attributable to our use of Ginsberg’s
definition of PTS as our primary outcome, because this
measure has been shown to capture more severe forms
of PTS.29 However, the incidence of PTS defined by
Villalta criteria (secondary outcome) was similar in
p=0·047
our study with that reported in previous prospective
studies.3,11,30 We did not identify that active ECS were
effective using either the Ginsberg or Villalta measure’s
p=0·60 definition of PTS. We believe it is a strength of our trial
that both measures were used to assess PTS, because
this enhances comparability of our results with those of
other studies.
p=0·38
Additional strengths of our trial are its large size,
multicentre design, 2 year length of follow-up, and that
several strategies were used to protect against bias,
p=0·55 including randomisation with allocation concealment,
use of a placebo stocking to achieve masking, and use of
validated instruments to assess PTS and quality of life.
5 10
Also, we measured stocking compliance throughout the
study and assessed masking at the end of each patient’s
participation on the trial.
Limitations of our study are that 114 (14%) of 803 patients
withdrew or were lost to follow-up; however, these rates
were similar in the two groups and consistent with our

pretrial projections. Adherence to study stockings tended
to diminish over follow-up, which could have affected
treatment efficacy. However, the results of our per-protocol
analyses focusing on frequent users and daily users, were
similar to that of our intention-to-treat analysis, which
increases confidence in our finding of no effect of active
ECS. We acknowledge that the subgroup results must be
interpreted with caution since our sample size calculation
did not include the detection of subgroup effects.
Although results of sensitivity analyses to account for
missing quality-of-life data did not differ from complete
case analysis, we acknowledge that quality of life of
patients who withdrew or were lost to follow-up might
have differed from those who remained in the study.
We used a number of strategies to reduce unmasking
of treatment assignment. Active and placebo stockings
looked identical. Study stockings were shipped directly to
the patients, who were instructed to not wear them to
study visits to maintain masking of allocation from
assessors.31 Most patients, research nurses, and site
investigators remained unaware of treatment allocation.
Although partial unmasking might have happened in the
active stocking group, because two-fifths of patients
correctly guessed their treatment assignment, this
further reinforces rather than weakens our finding of
lack of treatment effect of active ECS.
Our findings differ from those of two previous random-
ised trials (panel), which showed substantial benefit of
30–40 mm Hg ECS to prevent PTS after proximal DVT.10,11
These studies were open label, single centre, and smaller
than our study. In the study by Brandjes and colleagues10
of 194 patients randomly assigned to wear a made-to-
measure 40 mm Hg knee-length ECS for at least 2 years
versus no stocking, mild-to-moderate PTS (assessed with
a Villalta-like scale) occurred in 20% of patients versus
47%, and severe PTS in 11% versus 23%. In the study by
Prandoni and colleagues11 of 180 patients randomly
assigned to wear so-called off-the-rack 30–40 mm Hg
knee length ECS for 2 years versus no stocking, PTS
(assessed with Villalta’s scale, with positive criteria
required on at least two consecutive visits) was recorded
in 25% versus 49% of patients and severe PTS in 4%
versus 12%. In these studies, stockings were replaced
every 6 months, as in our study. The lower rates of PTS in
the treatment groups than the control groups in these
studies could be due to, at least in part, their open-label
design. Although these previous trials masked allocations
from assessors, assessment of PTS was based on both
patient-reported symptoms and clinician-assessed signs.
As apparent benefits of a treatment might derive from a
placebo effect, which typically is strongest in measures of
subjective symptoms,32 the use of a placebo stocking
control in our study was intended to account for a placebo
effect of active stockings. We sought other potential
reasons for differences between our results and those of
the previous studies. The characteristics of patients in
our trial (eg, age, sex distribution, DVT risk factors,
www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9
Articles
Panel: Research in context
Systematic review
At the time of applying for funding of the SOX trial, in September, 2003, we did a
computer database search for individual trials and systematic reviews of the use of
compression stockings started early after deep venous thrombosis (DVT) diagnosis to
prevent the post-thrombotic syndrome (PTS). The terms stockings, compression
stockings, post-thrombotic syndrome, and post-phlebitic syndrome were used to search
PubMed and the Cochrane Database of Systematic Reviews. Only one study was
identified: a trial by Brandjes and colleagues10 in which 194 patients with symptomatic
proximal DVT were randomly assigned to receive daily use of knee-length custom-made
40 mm Hg elastic compression stockings (ECS), applied within 2–3 weeks of DVT
diagnosis for at least 2 years, versus no stockings. Use of stockings reduced the incidence
of mild to moderate PTS from 47% to 20% and of severe PTS from 23% to 11%. In 2004,
after the SOX trial began, Prandoni and colleagues11 published the results of a trial of
off-the-rack 30–40 mm Hg ECS used for 2 years to prevent PTS after a first episode of
proximal DVT. OF 180 patients, those randomly assigned to receive ECS had a
24·5% incidence of PTS, compared with 49·1% in controls. Both of the above trials were
single centre, open-label studies. A new search of the scientific literature in May, 2013, did
not identify additional published trials of ECS used early after DVT to prevent PTS.
Interpretation
In a first, large (803 patients), multicentre, placebo-controlled trial, we noted that wearing
30–40 mm Hg graduated ECS did not reduce the incidence of PTS at 2 years in patients with
a first proximal DVT, compared with wearing placebo stockings. Similarly, ECS did not affect
the occurrence of venous ulcers, rate of recurrent venous thromboembolism, prevalence of
venous valvular reflux at 12 months, or generic or venous-disease-specific quality of life. Our
findings were consistent across subgroups and among frequent ECS users. Therefore, our
results do not support routine wearing of ECS after DVT to prevent PTS.
anatomical extent of DVT, and duration of anti-
coagulation) were similar to those of the previous studies.
Compliance with ECS might have been greater in the
previous trials than in our study, but because of differ-
ences in how often use was measured and reported in the
three studies, this is uncertain. Differences might relate
to the particular brand of active ECS used in our study,
but we believe this is unlikely since the compression
strength used was the same as in the previous trials.
We believe it is unlikely that our trial’s null results can
be attributed to a therapeutic benefit of placebo ECS,
because placebo stockings were manufactured to have no
therapeutic effect (5 mm Hg or less at the ankle), and the
2 year cumulative incidence of Villalta-defined PTS in
both the active and placebo stockings groups in our study
was similar to that in the control arms of the previous
trials that reported benefit of stockings.10,11
We believe that our results are generalisable to the broad
population of patients with proximal DVT in whom use of
ECS would be considered. As noted above, the charac-
teristics of patients in our trial were similar to those of the
previous ECS trials10,11 and to published cohorts and
population-based studies of patients with DVT.2,33
Our findings that ECS started at the time of acute
DVT do not prevent PTS are consistent with a small
randomised trial that used ECS 1 year after proximal
7
 Articles
DVT and identified no difference in rates of PTS
compared with wearing a sham stocking that was one to
two sizes too large.15 Similarly, in patients with proximal
DVT who wore ECS for 6 months and were then
randomly assigned to stopping stockings or using them
for an additional 18 months, there was no difference in
rates of PTS at 2 years.34 Although these and our results
suggest that ECS might not affect the natural history
of PTS development after DVT, whether compression
stockings might be of benefit to improve symptoms of
established PTS or of acute DVT warrants assessment in
future studies.
Contributors
SRK was involved in study design, data collection, data interpretation,
writing, and critical review and final approval of the report. PSW, MAR,
MJK, DRA, VT, and JSG were involved in study design, data collection,
and critical review and final approval of the report. SSh was involved in
study design, data analysis, data interpretation, and critical review and
final approval of the report. AHH was involved in data collection, data
analysis, data interpretation, writing, and critical review and final
approval of the report. TD and CH were involved in data analysis, data
interpretation, and critical review and final approval of the report. MJ,
SSo, M-JM, EY, RSm, SSc, JK, CK, IC, TW, CD, RH, SK, RSe, SR, SD,
LO, and TLO were involved in data collection and critical review and
final approval of the report.
SOX trial investigators
Collaborators: Canada E Lang, E Shulikovsky (Jewish General Hospital,
Montreal, QC; 138 patients randomly assigned to study groups);
M Forgie, C Hilliker, V Borsella, J Chen, F Hallé, A Levac, R Larose,
C Blais (The Ottawa Hospital, Ottawa, ON; 131); A Lazo-Langner,
M McLean, B Morrow, R Corpuz (London Health Sciences Centre,
London, ON; 66); B St-Jacques, S Finkenbine (Montreal General
Hospital, Montreal, QC; 56); M Dominquez, A Roussin, F Joyal,
V Daniel, S Paris, D Bélisle, D Forand (Hôpital Notre-Dame, Montreal,
QC; 52); B Gallant, L Gray, A MacNeil (Queen Elizabeth II Health
Sciences Centre, Halifax, NS; 46); S Bates, P Stevens (McMaster
University Medical Center, Hamilton, ON; 46); B Brien, A McLeod,
R Wu, M Dzyuba, S Jenkins (Toronto General Hospital, Toronto, ON;
39); S Sorensen, L Reimer, N Lounsbury (Victoria Heart Institute
Foundation, Victoria, BC; 36); J Eikelboom, L Rudd-Scott, M Zondag,
M Robinson (Hamilton Health Sciences–General, Hamilton, ON; 34);
D-T Nguyen, D Sylvestre, J Trinh Lu, L Chevalier (Hôpital
Maisonneuve-Rosemont, Montreal, QC; 25); K Mendelew, K McTavish,
K Nguyen (St Mary’s Hospital Center, Montreal, QC; 22); P Gross, A Lee,
L-A Linkins, J Weitz, T Winkworth, M Thompson, D Donovan
(Juravinski Hospital, Hamilton Health Sciences, Hamilton, ON; 21);
M Laurier, N Routhier, A-M Mansour, M Helou, G Grégoire, C Chagnon,
C Nadon (Hôpital du Sacré-Coeur, Montreal, QC; 15); G Drobot, J Arbez,
S Erikson-Nesmith (St Boniface General Hospital, Winnipeg, MB; 15);
R Delage, C Doyle, J Morin, P-F Leblond, C Petitclerc, G Cantin, C Jobin,
Y Hébert, J Poulin (CHA Hôpital de l’Enfant-Jésus, Montreal, QC; 13);
J Douketis, M Crowther, W Lim, T Schnurr (St Joseph’s Hospital,
Hamilton, ON; 12); R Jay, W Bartle, W Geerts, F Sealey, L Kaus
(Sunnybrook Hospital, Toronto, ON; 10); N Fortin (Hôpital Pierre-
Boucher, Montreal, QC; 4); K Riches, C Barber (Royal Victoria Hospital,
Montreal, QC; 3); F Spencer, T Lyon, D Magier, S Robinson (Hamilton
Health Sciences—Chedoke Division, Hamilton, ON; 2). USA H Gikas,
S Ellsworth (Henry Ford Hospital, Detroit, MI; 11); S Rathbun
(Oklahoma University Health Sciences Center, Oklahoma City, OK; 8);
MA Gleim, S Adams, C Mette (Duke University Medical Center,
Durham, NC; 1).
SOX trial coordinating centre: Center for Clinical Epidemiology, Jewish
General Hospital, Montreal, QC, Canada.
Statistical analysis: C Holcroft, T Ducruet (Center for Clinical
Epidemiology, Jewish General Hospital, Montreal, QC, Canada).
Independent adjudication committee: A Hirsch, M Blostein (Jewish
General Hospital, Montreal, QC, Canada).
8 www.thelancet.com Published online December 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61902-9
Data safety monitoring board: G Raskob, S Vesely, D Thompson
(Oklahoma University Health Sciences Center, Oklahoma City, OK,
USA); B L Davidson (Division of Pulmonary and Critical Care Medicine,
University of Washington School of Medicine, Seattle, WA, USA)
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
Funding for this study was provided by Canadian Institutes for Health
Research (grant number MCT 63142, MOP 102610), with active and
placebo stockings provided as in-kind support by Sigvaris Corp. SRK is
supported by a National Research Scientist award from the Fonds de
recherche du Québec—Santé. MAR is supported by a Career Investigator
award from the Heart and Stroke Foundation of Ontario and a Tier 1
Research Chair Award, Faculty of Medicine, University of Ottawa. CK is
supported by a Career Investigator award from the Heart and Stroke
Foundation of Ontario. JSG is supported by a Career Investigator award
from the Heart and Stroke Foundation of Ontario and is a recipient of the
David Braley and Nancy Gordon Chair for Investigation of
Thromboembolic Diseases. We gratefully acknowledge the contribution
of the SOX Trial Central Trial Coordinators Tatiana Vydykhan (study
start-up to January, 2007), Hadia Shbaklo (January, 2007, to May, 2008),
and Adrielle Houweling (May, 2008, to present). We thank
Monika Hudoba, Lindsay Young, and Ria Giakoumakis of Sigvaris Corp
for their assistance with distribution of study stockings during the trial.
We thank Russell Steele, Department of Mathematics and Statistics,
McGill University and Centre for Clinical Epidemiology, Jewish General
Hospital for his suggestions on missing data analyses.
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